The present invention concerns the use of IL-5 inhibiting 6-azauracil derivatives in the manufacture of a medicament useful for treating eosinophil-dependent inflammatory diseases. It further relates to certain novel 6-azauracil derivatives, to processes for their preparation and compositions comprising them.
Eosinophil influx, leading to subsequent tissue damage, is an important pathogenic event in bronchial asthma and allergic diseases. The cytokine interleukin-5 (IL-5), produced mainly by T lymphocytes as a glycoprotein, induces the differentiation of eosinophils in bone marrow and, primes eosinophils for activation in peripheral blood and sustains their survival in tissues. As such, IL-5 plays a critical role in the process of eosinophilic inflammation. Hence, the possibility that inhibitors of IL-5 production would reduce the production, activation and/or survival of eosinophils provides a therapeutic approach to the treatment of bronchial asthma and allergic diseases such as, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, and also other eosinophil-dependent inflammatory diseases.
Steroids, which strongly inhibit IL-5 production in vitro, have long been used as the only drugs with remarkable efficacy for bronchial asthma and atopic dermatitis, but they cause various serious adverse reactions such as diabetes, hypertension and cataracts. Therefore, it would be desirable to find non-steroidal compounds having the ability to inhibit IL-5 production in human T-cells and which have little or no adverse reactions.
U.S. Pat. No. 4,631,278 discloses xcex1-aryl-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-benzeneacetonitriles and U.S. Pat. No. 4,767,760 discloses 2-(substituted phenyl)-1,2,4-triazine-3,5(2H,4H)-diones, all having anti-protozoal activity, in particular, anti-coccidial activity. Unexpectedly, the 6-azauracil derivatives of the present invention, including said art-known 1,2,4-triazinedione derivatives, prove to be potent inhibitors of the production of IL-5.
The present invention is concerned with the use of compounds of formula 
the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein:
p represents an integer being 0, 1, 2, 3 or 4;
q represents an integer being 0, 1, 2, 3, 4 or 5;
R1 represents hydrogen, C1-6alkyl, mono- or di(C1-6alkyl)aminoC1-6alkyloxy, mercapto, C1-6alkylthio, C3-7cycloalkyl, aryl or C1-6alkyl substituted with mono- or di(C1-6alkyl)amino, C1-6alkyloxy, aryl or Het;
R2 represents cyano or a radical of formula xe2x80x94C(xe2x95x90X)xe2x80x94Yxe2x80x94R5; wherein
X represents O or S;
Y represents O, S, NR6 or a direct bond;
R5 represents hydrogen; C1-6alkyl; C3-7cycloalkyl; aryl or C1-6alkyl substituted with aryl, hydroxy or Het; and where Y is a direct bond, R5 may also be halo or Het;
R6 represents hydrogen, C1-6alkyl, C1-6alkyloxy or arylC1-6alkyl;
each R3 independently represents halo, haloC1-6alkyl, C1-6alkyl, hydroxy, C1-6alkyloxy, C1-6alkylcarbonyloxy, mercapto, C1-6alkylthio, C1-6alkylsulfonyl, C1-6alkylsulfinyl, haloC1-6alkylsulfonyl, aryl, cyano, nitro, amino, mono- and di(C1-6alkyl)amino or (C1-6alkylcarbonyl)amino;
each R4 independently represents halo, haloC1-6alkyl, C1-6alkyl, hydroxy, C1-6alkyloxy, C1-6alkylcarbonyloxy, mercapto, C1-6alkylthio, C1-6alkylsulfonyl, C1-6alkylsulfinyl, haloC1-6alkylsulfonyl, aryl, cyano, nitro, amino, mono- and di(C1-6alkyl)amino or (C1-6alkylcarbonyl)amino;
aryl represents phenyl or phenyl substituted with one, two or three substituents selected from the group comprising halo, C1-6alkyl, C1-6alkyloxy, haloC1-6alkyl, hydroxy, mercapto, C1-6alkylthio, C1-6alkylsulfonyl, C1-6alkylsulfonyloxy, C1-6alkylsulfinyl, haloC1-6alkylsulfonyl, nitro, cyano, amino, mono- and di(C1-6alkyl)amino and C1-6alkylcarbonylamino; and
Het represents a heterocycle selected from pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trithianyl, triazinyl, benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl, benzthiazolyl, benzoxazolyl, indolyl, isoindolyl, indolinyl, purinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phtalazinyl, quinazolinyl, quinoxalinyl and thiazolopyridinyl; said heterocycles each independently may be substituted with one, two or three substituents selected from hydroxy, mercapto, C1-4alkyl, C1-4alkyloxy, cyano, amino, nitro, mono- or di(C1-4alkyl)amino, mono- or di(C1-4alkyl)aminocarbonyl, mono- or di(aryl)amino, halo, haloC1-4alkyl, C1-4alkyloxycarbonyl, aryl, furanyl, thienyl, pyridinyl, piperidinyl, C1-4alkylcarbonylpiperidinyl and C1-4alkyl substituted with hydroxy, C1-4alkyloxy, aryl, piperidinyl, amino, mono- or di(C1-4alkyl)amino or C3-7cycloalkyl;
in the manufacture of a medicament useful for treating eosinophil-dependent inflammatory diseases.
The compounds of formula (I) are deemed novel, provided that the xcex1-aryl-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetonitriles published in U.S. Pat. No. 4,631,278 and the 2-(substituted phenyl)-1,2,4-triazine-3,5(2H,4H)-diones published in U.S. Pat. No. 4,767,760 are excluded therefrom.
Thus, the invention also concerns novel compounds of formula 
the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein p, q, R1, R2, R3 and R4 are as defined in the compounds of formula (I), provided that the following conditions apply to the variables R3a, R3b, R3c, R4a, R4b, R4c, R1 and R2 in the compounds with general structure: 
a) if R3a, R3b are chloro; R4a is 4-chloro; and R1, R3c, R4b and R4c are hydrogen; then R2 is other than aminocarbonyl, carboxyl, chlorocarbonyl, 1-piperidinylcarbonyl, methoxycarbonyl, methylaminocarbonyl, 1-pyrrolidinylcarbonyl, 4-methyl-1-piperazinylcarbonyl, methylcarbonyl, NH2xe2x80x94C(xe2x95x90S)xe2x80x94, phenylcarbonyl; and
b) if R3a is chloro; R4a is 4-chloro; and R1, R3b, R3c, R4b and R4c are hydrogen; then R2 is other than aminocarbonyl, carboxyl, NH2xe2x80x94C(xe2x95x90S)xe2x80x94, chlorocarbonyl, methylaminocarbonyl, (4-methylcarbonyl-1-piperazinyl)carbonyl, (4-phenylmethyl-1-piperazinyl)carbonyl or methyloxycarbonyl; and
c) if the combination of R1, R3a, R3b, R3c, R4a, R4b and R4c is one of the following
then R2 is other than cyano.
As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; C3-7cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C1-4alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylethyl and the like; C1-6alkyl is meant to include C1-4alkyl and the higher homologues thereof having 5 or 6 carbon atoms such as, for example, pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the like; haloC1-6alkyl is defined as polyhalosubstituted C1-6alkyl, in particular C1-6alkyl substituted with 1 to 6 halogen atoms, more in particular difluoro- or trifluoromethyl.
Het is meant to include all the possible isomeric forms of the heterocycles mentioned in the definition of Het, for instance, pyrrolyl includes 2H-pyrrolyl; triazolyl includes 1,2,4-triazolyl and 1,3,4-triazolyl; oxadiazolyl includes 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl and 1,3,4 oxadiazolyl; thiadiazolyl includes 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl and 1,3,4 thiadiazolyl; pyranyl includes 2H-pyranyl and 4H-pyranyl; thiazolopyridinyl includes thiazolo[5,4-b]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[5,4-d]pyridinyl and thiazolo[5,4-e]pyridinyl.
The heterocycles represented by Het may be attached to the remainder of the molecule of formula (I) through any ring carbon or heteroatom as appropriate. Thus, for example, when the heterocycle is imidazolyl, it may be a 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl; when it is triazolyl, it may be 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,3,4-triazol-1-yl and 1,3,4-triazol-2-yl; when it is benzthiazolyl, it may be 2-benzthiazolyl, 4-benzthiazolyl, 5-benzthiazolyl, 6-benzthiazolyl and 7-benzthiazolyl; when it is thiazolopyridinyl, it may be thiazolo[5,4-b]pyridin-2-yl, thiazolo[5,4-b]pyridin-4-yl, thiazolo[5,4-b]pyridin-5-yl, thiazolo[5,4-b]pyridin-6-yl, thiazolo[5,4-c]pyridin-2-yl, thiazolo[5,4-c]pyridin-4-yl, thiazolo[5,4-c]pyridin-5-yl, thiazolo[5,4-c]pyridin-7-yl, thiazolo[5,4-d]pyridin-2-yl, thiazolo[5,4-d]pyridin-4-yl, thiazolo[5,4-d]pyridin-6-yl, thiazolo[5,4-d]pyridin-7-yl, thiazolo[5,4-e]pyridin-2-yl, thiazolo[5,4-e]pyridin-5-yl, thiazolo[5,4-e]pyridin-6-yl and thiazolo[5,4-e]pyridin-7-yl.
The pharmaceutically acceptable addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, for example, hydrohalic acids, e.g. hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely the salt form can be converted by treatment with alkali into the free base form.
The compounds of formula (I) containing acidic protons may be converted into their therapeutically active non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely the salt form can be converted by treatment with acid into the free acid form.
The term addition salt also comprises the hydrates and solvent addition forms which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
The N-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide.
Some of the compounds of formula (I) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
The term xe2x80x9cstereochemically isomeric formsxe2x80x9d as used hereinbefore defines all the possible stereoisomeric forms in which the compounds of formula (I) can exist. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More in particular, stereogenic centers may have the R- or S-configuration, used herein in accordance with Chemical Abstracts nomenclature. Stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be embraced within the scope of this invention.
The compounds of formula (I) and some of the intermediates in the present invention contain one or more asymmetric carbon atoms. The pure and mixed stereochemically isomeric forms of the compounds of formula (I) are intended to be embraced within the scope of the present invention.
Whenever used hereinafter, the term xe2x80x9ccompounds of formula (I)xe2x80x9d is meant to also include their N-oxide forms, their pharmaceutically acceptable addition salts, and their stereochemically isomeric forms.
The numbering of the phenyl ring bearing substituent R4 is given hereinbelow and is used herein as such when indicating the position of the R4 substituents on said phenyl ring, unless otherwise indicated. 
The carbon atom bearing the two phenyl rings and the R1 and R2 substituents will be referred herein as the central chiral carbon atom.
A suitable subgroup consists of those compounds of formula (I) or (Ixe2x80x2) wherein Het is other than pyrrolidinyl.
A special group of compounds are those compounds of formula (I) or (Ixe2x80x2) wherein R2 is a radical of formula xe2x80x94C(xe2x95x90X)xe2x80x94Yxe2x80x94R5 wherein Y is a direct bond and R5 is Het.
Another special group of compounds are those compounds of formula (I) or (Ixe2x80x2) wherein R1 is mono- or di(C1-6alkyl)aminoC1-6alkyloxy, mercapto, C1-6alkylthio or C1-6alkyl substituted with mono- or di(C1-6alkyl)amino, C1-6alkyloxy or Het.
An interesting group of compounds are those compounds of formula (I) or (Ixe2x80x2) wherein the 6-azauracil moiety is connected to the phenyl ring in the para or meta position relative to the central chiral carbon atom, particularly in the para position.
Another interesting group of compounds are those compounds of formula (I) or (Ixe2x80x2) wherein R2 is cyano.
Still another interesting group of compounds are those compounds of formula (1) or (Ixe2x80x2) wherein R2 is a radical of formula xe2x80x94C(xe2x95x90X)xe2x80x94Yxe2x80x94R5 wherein R5 is hydrogen, C1-6alkyl or aryl while Y is O, S or NR6 wherein R6 is hydrogen or C1-6alkyloxy; or R5 is aryl, C1-6alkyl, halo, Het or C1-6alkyl substituted with aryl while Y is a direct bond. Suitably, Het is optionally substituted piperazinyl, imidazolyl, thiazolyl or benzothiazolyl.
Yet another interesting group of compounds are those compounds of formula (I) or (Ixe2x80x2) wherein R1 is hydrogen, aryl, C1-6alkyl, mono- or di(C1-6alkyl)aminoC1-6alkyl or HetC1-6alkyl.
Particular compounds are those compounds of formula (I) or (Ixe2x80x2) wherein R3 and R4 each independently are halo, haloC1-6alkyl, hydroxy, C1-6alkyl, C1-6alkyloxy, C1-6alkylcarbonyloxy or aryl, more in particular, bromo, chloro, fluoro, trifluoromethyl, methyl, hydroxy, methoxy, methylcarbonyloxy or phenyl.
Other particular compounds are those compounds of formula (I) or (Ixe2x80x2) wherein p is 0, 1 or 2, and q is 0, 1, 2 or 3, more in particular, p and q each independently are 1 or 2.
Preferred compounds are those compounds of formula (I) or (Ixe2x80x2) wherein q is 1 or 2 and one R4 substituent, preferably selected from chloro, fluoro, methyl, hydroxy, methoxy, methylcarbonyloxy and phenyl, is in the 4 position.
Other preferred compounds are those compounds of formula (I) or (Ixe2x80x2) wherein p is 1 or 2 and the one or two R3 substituents, preferably selected from bromo, chloro, methyl, methoxy or trifluoromethyl, are in the ortho position relative to the central chiral carbon atom.
More preferred compounds are those compounds of formula (I) or (Ixe2x80x2) wherein the 6-azauracil moiety is in the para position relative to the central chiral carbon atom; p is 1 or 2 and one R3 substituent is chloro positioned ortho relative to the central chiral carbon atom; q is 1 or 2 and one R4 substituent is chloro in the 4 position.
Particularly preferred compounds are those compounds as described hereinabove as more preferred compounds wherein R2 is cyano or a radical of formula xe2x80x94C(xe2x95x90X)xe2x80x94Yxe2x80x94R5 wherein Y is a direct bond.
The compounds of the present invention can generally be prepared as described in U.S. Pat. Nos. 4,631,278 and 4,767,760.
In particular, the compounds of formula (Ixe2x80x2) can be prepared by cyclizing an intermediate of formula (II) and eliminating the group E from the thus obtained dione of formula (III). 
A suitable way of eliminating group E, which is for example a carboxyl group, may be reacting intermediate of formula (III) with mercaptoacetic acid or a functional derivative thereof.
The compounds of formula (Ixe2x80x2) may also be prepared by eliminating the protective group P in the intermediates of formula (IV). 
A suitable way of eliminating group P, which is for example a alkyloxyalkyloxyalkyl moiety, may be reacting intermediate of formula (IV) with a acid or an acid mixture such as hydrochloric acid, acetic acid or a mixture thereof. Alternatively, the protective group P may be removed by reacting an intermediate of formula (IV) with a suitable reagent such as, for example, boron tribromide, in a reaction-inert solvent such as, for example, dichloromethane.
The compounds of formula (Ixe2x80x2) wherein R2 is cyano, said compounds being represented by formula (Ixe2x80x2-a), can be prepared by converting the hydroxyl function of an intermediate of formula (V) into a suitable leaving group W such as, for example, a halogen or a sulfonyloxy group, and subsequently converting said leaving group W in the thus formed intermediate of formula (VI) into a nitrile function. 
The compounds of formula (Ixe2x80x2) wherein R1 is hydrogen and R2 is cyano, said compounds being represented by formula (Ixe2x80x2-a-1), can be prepared by reacting the carbonyl group in the intermediates of formula (VII) with a suitable reagent such as, for example, 1-[(isocyanomethyl)sulfonyl]-4-methylbenzene or a functional derivative thereof. 
The compounds of formula (I) can be converted into each other following art-known procedures of functional group transformation and are described in U.S. Pat. No. 4,767,760, Some interesting group transformation reactions described therein are mentioned hereinafter.
In order to simplify the structural representation of the compounds of formula (Ixe2x80x2), the group 
will hereinafter be represented by the symbol D.
The compounds of formula (Ixe2x80x2-a) may be partially or completely hydrolyzed, thus yielding compounds of formula (Ixe2x80x2) wherein R2 is an aminocarbonyl or a carboxyl group, the former being represented by formula (Ixe2x80x2-f), the latter by (Ixe2x80x2-b). The compounds of formula (Ixe2x80x2-f) can further be hydrolized to compounds of formula (Ixe2x80x2-b).
The compounds of formula (Ixe2x80x2-a) may also be converted to compounds of formula (Ixe2x80x2-g) wherein R2 is an aminothioxomethyl group.
The acids of formula (Ixe2x80x2-b) can be converted to the corresponding acylhalides of formula (Ixe2x80x2-c). Said acylhalides of formula (Ixe2x80x2-c) can further be derivatized using HN(R5)(R6) to the corresponding amides of formula (Ixe2x80x2-d) which in turn may further be reacted to a heteroaryl ketone of formula (Ixe2x80x2-e) using a suitable metal alkyl such as, for example, butyl lithium, in a reaction-inert solvens such as, for example, tetrahydrofuran, hexane, diethylether or a mixture thereof. The latter reaction may conveniently be performed under an inert atmosphere such as, for example, oxygen-free nitrogen, and at a low reaction temperature, preferably at about xe2x88x9270xc2x0 C. The acylhalides of formula (Ixe2x80x2-c) can also be reacted with a Grignard reagent, e.g. RMgX, wherein X is a suitable counter ion such as a halogen, and R is C3-7cycloalkyl or C1-6alkyl optionally substituted with aryl or Het, thus obtaining intermediates of formula (Ixe2x80x2-h). 
In addition, the compounds of formula (Ixe2x80x2) may be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. tert-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
Pure stereochemically isomeric forms of the compounds of formula (Ixe2x80x2) may be obtained by the application of art-known procedures. Diastereomers may be separated by physical methods such as selective crystallization and chromatographic techniques, e.g. counter-current distribution, liquid chromatography and the like.
The compounds of formula (Ixe2x80x2) as prepared in the hereinabove described processes are generally racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of formula (Ixe2x80x2) which are sufficiently basic or acidic may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid respectively with a suitable chiral base. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali or acid. An alternative manner of separating the enantiomeric forms of the compounds of formula (Ixe2x80x2) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
An alternative manner of separating the enantiomeric forms of the compounds of formula (I) and intermediates involves liquid chromatography, in particular liquid chromatography using a chiral stationary phase.
A number of intermediates and starting materials in the foregoing preparations are commercially available or are known compounds which may be prepared according to art-known methodologies of preparing said or similar intermediates. In particular, the preparation of the intermediates of formula (II), (IV), (V) and (VII) are described in U.S. Pat. Nos. 4,631,278, 4,767,760, 3,883,527 and Carroll et al. in J. Med. Chem. 1983, 26, 96-100.
IL-5, also known as eosinophil differentiating factor (EDF) or eosinophil colony stimulating factor (Eo-CSF), is a major survival and differentiation factor for eosinophils and basophils and therefore thought to be a key player in eosinophil infiltration into tissues. There is ample evidence that eosinophil influx is an important pathogenic event in bronchial asthma and allergic diseases such as, cheilitis, irritable bowel disease, eczema, urticaria, vasculitis, vulvitis, winterfeet, atopic dermatitis, pollinosis, allergic rhinitis and allergic conjunctivitis; and other inflammatory diseases, such as eosinophilic syndrome, allergic angiitis, eosinophilic fasciitis, eosinophilic pneumonia, PIE syndrome, idiopathic eosinophilia, eosinophilic myalgia, Crohn""s disease, ulcerative colitis and the like diseases.
The present compounds also inhibit the production of other chemokines such as monocyte chemotactic protein-1 and -3 (MCP-1 and MCP-3). MCP-1 is known to attract both T-cells, in which IL-5 production mainly occurs, and monocytes, which are known to act synergetically with eosinophils (Carr et al., 1994, Immunology, 91, 3652-3656). MCP-3 also plays a primary role in allergic inflammation as it is known to mobilize and activate basophil and eosinophil leukocytes (Baggiolini et al., 1994, immunology Today, 15(3), 127-133).
The present compounds have no or little effect on the production of other chemokines such as IL-1, IL-2, IL-3, IL-4, IL-6, IL-10, xcex3-interferon (IFN-xcex3) and granulocyte-macrophage colony stimulating factor (GM-CSF) indicating that the present IL-5 inhibitors do not act as broad-spectrum immunosuppressives.
The selective chemokine inhibitory effect of the present compounds can be demonstrated by in vitro chemokine measurements in human blood of which the test results for IL-5 are presented in the experimental part hereinafter. In vivo observations such as the inhibition of eosinophilia in mouse ear, the inhibition of blood eosinophilia in the Ascaris mouse model; the reduction of serum IL-5 protein production and splenic IL-5 mRNA expression induced by anti-CD3 antibody in mice and the inhibition of allergen- or Sephadex-induced pulmonary influx of eosinophils in guinea-pig are indicative for the usefulness of the present compounds in the treatment of eosinophil-dependent inflammatory diseases.
The present inhibitors of IL-5 production are orally active compounds.
In view of the above pharmacological properties, the present compounds can be used in the manufacture of a medicament for treating eosinophil-dependent inflammatory diseases as mentioned hereinabove, in particular bronchial asthma, atopic dermatitis, allergic rhinitis and allergic conjunctivitis. The present invention also involves two groups of novel compounds for use as a medicine. One of said groups consists of those compounds of formula (Ixe2x80x2) wherein R1 is mono- or di(C1-6alkyl)aminoC1-6alkyloxy, mercapto, C1-6alkylthio or C1-6alkyl substituted with mono- or di(C1-6alkyl)amino, C1-6alkyloxy or Het, the other group consists of those compounds of formula (Ixe2x80x2) wherein R2 is a radical of formula xe2x80x94C(xe2x95x90X)xe2x80x94Yxe2x80x94R5 wherein Y is a direct bond and R5 is Het.
In view of the utility of the compounds of formula (I), there is provided a method of treating warm-blooded animals, including humans, suffering from eosinophil-dependent inflammatory diseases, in particular bronchial asthma, atopic dermatitis, allergic rhinitis and allergic conjunctivitis. Said method comprises the systemic or topical administration of an effective amount of a compound of formula (I), a N-oxide form, a pharmaceutically acceptable addition salt or a possible stereoisomeric form thereof, to warm-blooded animals, including humans.
The present invention also provides compositions for treating eosinophil-dependent inflammatory diseases comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or diluent together with instructions for the use thereof for the treatment of an eosinophil-dependent inflammatory disease.
In particular, the present invention provides compositions for treating eosinophil-dependent inflammatory diseases comprising a therapeutically effective amount of a compound of formula (Ixe2x80x2) wherein R2 is a radical of formula xe2x80x94C(xe2x95x90X)xe2x80x94Yxe2x80x94R5 wherein Y is a direct bond and R5 is Het or a compound of formula (Ixe2x80x2) wherein R1 is mono- or di(C1-6alkyl)aminoC1-6alkyloxy, mercapto, C1-6alkylthio or C1-6alkyl substituted with mono- or di(C1-6alkyl)amino, C1-6alkyloxy or Het, and a pharmaceutically acceptable carrier or diluent.
To prepare the aforementioned pharmaceutical compositions, a therapeutically effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for systemic administration such as oral, percutaneous, or parenteral administration; or topical administration such as via inhalation, a nose spray, eye drops or via a cream, gel, shampoo or the like. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable solutions containing compounds of formula (I) may be formulated in an oil for prolonged action. Appropriate oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soy bean oil, synthetic glycerol esters of long chain fatty acids and mixtures of these and other oils. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment. As appropriate compositions for topical application there may be cited all compositions usually employed for topically administering drugs e.g. creams, gellies, dressings, shampoos, tinctures, pastes, ointments, salves, powders and the like. Application of said compositions may be by aerosol, e.g. with a propellent such as nitrogen, carbon dioxide, a freon, or without a propellent such as a pump spray, drops, lotions, or a semisolid such as a thickened composition which can be applied by a swab. In particular, semisolid compositions such as salves, creams, gellies, ointments and the like will conveniently be used.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
Preferred compositions are those compositions containing a novel compound of formula (Ixe2x80x2) wherein R2 is a radical of formula xe2x80x94C(xe2x95x90X)xe2x80x94Yxe2x80x94R5 wherein Y is a direct bond and R5 is Het, or a novel compound of formula (Ixe2x80x2) wherein R1 is mono- or di(C1-6alkyl)amino-C1-6alkyloxy, mercapto, C1-6alkylthio or C1-6alkyl substituted with mono- or di(C1-6alkyl)amino, C1-6alkyloxy or Het, and are in dosage unit form, comprising per dosage unit an effective quantity of active ingredient in admixture with suitable carriers.
In order to enhance the solubility and/or the stability of the compounds of formula (I) in pharmaceutical compositions, it can be advantageous to employ xcex1-, xcex2- or xcex3-cyclodextrins or their derivatives. Also co-solvents such as alcohols may improve the solubility and/or the stability of the compounds of formula (I) in pharmaceutical compositions. In the preparation of aqueous compositions, addition salts of the subject compounds are obviously more suitable due to their increased water solubility.
Appropriate cyclodextrins are xcex1-, xcex2-, xcex3-cyclodextrins or ethers and mixed ethers thereof wherein one or more of the hydroxy groups of the anhydroglucose units of the cyclodextrin are substituted with C1-6alkyl, particularly methyl, ethyl or isopropyl, e.g. randomly methylated xcex2-CD; hydroxyC1-6alkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxyC1-6alkyl, particularly carboxymethyl or carboxyethyl; C1-6alkylcarbonyl, particularly acetyl; C1-6alkyloxycarbonylC1-6alkyl or carboxy-C1-6alkyloxyC1-6alkyl, particularly carboxymethoxypropyl or carboxyethoxypropyl; C1-6alkylcarbonyloxyC1-6alkyl, particularly 2-acetyloxypropyl. Especially noteworthy as complexants and/or solubilizers are xcex2-CD, randomly methylated xcex2-CD, 2,6-dimethyl-xcex2-CD, 2-hydroxyethyl-xcex2-CD, 2-hydroxyethyl-xcex3-CD, 2-hydroxypropyl-xcex3-CD and (2-carboxymethoxy)propyl-xcex2-CD, and in particular 2-hydroxypropyl-xcex2-CD (2-HP-xcex2-CD).
The term mixed ether denotes cyclodextrin derivatives wherein at least two cyclodextrin hydroxy groups are etherified with different groups such as, for example, hydroxy-propyl and hydroxyethyl.
Due to their high degree of selectivity as IL-5 inhibitors, the compounds of formula (I) as defined above, are also useful to mark or identify receptors. To this purpose, the compounds of the present invention need to be labelled, in particular by replacing, partially or completely, one or more atoms in the molecule by their radioactive isotopes. Examples of interesting labelled compounds are those compounds having at least one halo which is a radioactive isotope of iodine, bromine or fluorine; or those compounds having at least one 11C-atom or tritium atom.
One particular group consists of those compounds of formula (I) wherein R3 and/or R4 are a radioactive halogen atom. In principle, any compound of formula (I) containing a halogen atom is prone for radiolabelling by replacing the halogen atom by a suitable isotope. Suitable halogen radioisotopes to this purpose are radioactive iodides, e.g. 122I, 123I, 125I, 131I; radioactive bromides, e.g. 75Br, 76Br, 77Br and 82Br, and radioactive fluorides, e.g. 18F. The introduction of a radioactive halogen atom can be performed by a suitable exchange reaction or by using any one of the procedures as described hereinabove to prepare halogen derivatives of formula (I).
Another interesting form of radiolabelling is by substituting a carbon atom by a 11C-atom or the substitution of a hydrogen atom by a tritium atom.
Hence, said radiolabelled compounds of formula (I) can be used in a process of specifically marking receptor sites in biological material. Said process comprises the steps of (a) radiolabelling a compound of formula (I), (b) administering this radiolabelled compound to biological material and subsequently (c) detecting the emissions from the radiolabelled compound. The term biological material is meant to comprise every kind of material which has a biological origin. More in particular this term refers to tissue samples, plasma or body fluids but also to animals, specially warm-blooded animals, or parts of animals such as organs.
The radiolabelled compounds of formula (I) are also useful as agents for screening whether a test compound has the ability to occupy or bind to a particular receptor site. The degree to which a test compound will displace a compound of formula (I) from such a particular receptor site will show the test compound ability as either an agonist, an antagonist or a mixed agonist/antagonist of said receptor.
When used in in vivo assays, the radiolabelled compounds are administered in an appropriate composition to an animal and the location of said radiolabelled compounds is detected using imaging techniques, such as, for instance, Single Photon Emission Computerized Tomography (SPECT) or Positron Emission Tomography (PET) and the like. In this manner the distribution of the particular receptor sites throughout the body can be detected and organs containing said receptor sites can be visualized by the imaging techniques mentioned hereinabove. This process of imaging an organ by administering a radiolabelled compound of formula (I) and detecting the emissions from the radioactive compound also constitutes a part of the present invention.
A suitable therapeutically effective daily amount would be from 0.01 mg/kg to 50 mg/kg body weight, in particular from 0.05 mg/kg to 10 mg/kg body weight. A method of treatment may also include administering the active ingredient on a regimen of between two or four intakes per day.